JP2017501228A - Opioid antagonist preparation - Google Patents

Abstract

In certain embodiments, the present invention provides a solid controlled release dosage form comprising a core comprising a core portion of an opioid antagonist, and a shell enclosing the core and comprising a shell portion of the opioid antagonist. Wherein the release characteristics of the core portion of the opioid antagonist are different from the release characteristics of the shell portion of the opioid antagonist, and are directed to the solid controlled release dosage form.

Description

  The present invention relates to a pharmaceutical formulation comprising an opioid antagonist. In certain embodiments, the formulations provide for the prevention and / or treatment of opioid agonist-induced adverse effects.

  Opioid agonists such as morphine, oxycodone, and hydrocodone are generally prescribed to treat both acute and chronic pain because their action at opioid receptors can result in effective pain relief. However, the stimulatory effects of certain opioid agonists on certain receptors can cause adverse pharmacodynamic reactions, including impaired bowel dysfunction, which can be manifested, for example, by decreased gastric motility, delayed gastric emptying, constipation, bloating and convulsions There is also sex. Other adverse pharmacodynamic reactions associated with opioid treatment include nausea, vomiting, lethargy, dizziness, respiratory depression, headache, dry mouth, sedation, sweating, asthenia, hypotension, discomfort, delirium, pupil reduction, and so on Examples include mania, urticaria, urinary stagnation, hyperalgesia, allodynia, physical dependence and tolerance.

  The opioid-induced adverse pharmacodynamic response in patients receiving opioid therapy for pain management can be particularly troublesome because these patients are already trying to manage severe pain. Adds discomfort to adverse effects and may increase pain. In some cases, the adverse effects are so extreme that the patient may cease using rather than continue to use opioids and suffer from such adverse effects.

  Opioid agonist pharmaceutical dosage forms may also be the subject of abuse. For example, a particular dose of opioid agonist may be more potent when administered parenterally compared to administering the same dose orally. Some formulations may be tampered with to provide formulations containing opioid agonists therein for abuse. Controlled release opioid agonist formulations contain an opioid contained therein so that they are immediately released when pulverized by a drug abuser or extracted with a solvent (eg, ethanol) and administered orally or parenterally. Certain formulations may be provided.

  There remains a need in the art for compositions and methods for preventing or treating opioid-induced adverse pharmacodynamic responses. There is also a need in the art for compositions and methods for preventing the abuse of opioid analgesics.

  The references described herein are incorporated by reference in their entirety for all purposes.

  It is an object of certain embodiments of the invention to provide a solid controlled release dosage form comprising an opioid antagonist that cannot be abused.

  It is an object of certain embodiments of the invention to provide a solid controlled release dosage form comprising an anti-modified opioid antagonist.

  It is an object of certain embodiments of the present invention to provide a solid controlled release dosage form comprising an opioid analgesic and an opioid antagonist that cannot be milled.

  It is an object of certain embodiments of the present invention to provide solid controlled release dosage forms comprising opioid analgesics and opioid antagonists that are less susceptible to opioid-induced adverse pharmacodynamic responses than other dosage forms. .

  It is an object of certain embodiments of the invention to provide a solid controlled release dosage form comprising an opioid antagonist directed to the release of at least a portion of the antagonist in the colon of a human subject.

  It is an object of certain embodiments of the present invention to provide solid controlled release dosage forms comprising opioid antagonists and opioid analgesics that are less likely to be abused parenterally than other dosage forms.

  It is an object of certain embodiments of the present invention to provide solid controlled release dosage forms comprising opioid antagonists and opioid analgesics that are less susceptible to intranasal abuse than other dosage forms.

  It is an object of certain embodiments of the present invention to provide solid controlled release dosage forms comprising opioid antagonists and opioid analgesics that are less likely to be abused orally than other dosage forms.

  Furthermore, it is an object of certain embodiments of the present invention to provide solid controlled release dosage forms comprising opioid analgesics and opioid antagonists that are less likely to be diverted than other dosage forms.

  Furthermore, it is a specific aspect of the invention to provide a method of treating pain in human patients with a solid controlled release dosage form comprising opioid analgesics and opioid antagonists while reducing the potential for abuse of the dosage form. This is the purpose of the embodiment.

  Furthermore, treating a disease or condition (eg, pain) by administering a solid controlled release dosage form as disclosed herein to a patient in need of treatment may be a specific implementation of the present invention. It is the purpose of the form.

  Furthermore, it is an object of certain embodiments of the invention to provide a method of making an oral dosage form of an active agent (eg, opioid analgesic) as disclosed herein.

  Furthermore, it is an object of certain embodiments of the invention to provide the use of a pharmaceutical agent (eg, an opioid analgesic) in the manufacture of a dosage form for the treatment of a disease state (eg, pain).

  It is another objective of certain embodiments of the invention to provide for the use of a pharmaceutical agent (eg, an opioid antagonist) for the preparation of any of the pharmaceutical agents disclosed herein.

  These objects and others are achieved by the present invention, and in certain embodiments, a core that includes a first portion of an opioid antagonist, an envelope that encloses the core, and a second portion of the opioid antagonist. And a shell containing, wherein the release characteristics of the first portion of the opioid antagonist are different from the release characteristics of the second opioid antagonist. In certain aspects of the invention, the dosage forms disclosed herein further comprise an opioid agonist.

  In certain embodiments, the present invention is directed to a solid controlled release dosage form comprising a core comprising a first portion of an opioid antagonist and a shell free of an antagonist encapsulating said core. In certain embodiments of the invention, the opioid agonist is included in one or more of the cores or shells.

  In certain embodiments, the invention is directed to a method of treating pain in a subject in need of treatment comprising administering to the subject a solid controlled release dosage form as disclosed herein. .

  In certain embodiments, the present invention comprises a solid comprising preparing a core comprising a first portion of an opioid antagonist and enclosing the core with a shell comprising a second portion of the opioid antagonist. For methods of preparing a controlled release dosage form, the release profile of the first portion of the opioid antagonist is different from the release profile of the second opioid antagonist.

  In certain embodiments, the invention prepares a core that includes a first portion of an opioid antagonist dispersed in a first matrix material, and a second of the opioid antagonist dispersed in a second matrix material. Directed to a method of preparing a solid controlled release dosage form comprising wrapping the core with a shell comprising two portions, wherein the release profile of the first portion of the opioid antagonist is that of the second opioid antagonist. Different from release characteristics.

  The term “zero order release rate” refers to the rate of active agent released from a dosage form that is relatively constant over a period of time, regardless of the remaining active agent concentration in the dosage form. A dosage form exhibiting a zero order release rate will be relatively linear in a graphical representation of the ratio of active agent released over time. In certain embodiments of the invention, a “substantially zero order release” is a dosage form having an amount of active release agent that is within 20% proportional to an elapsed time of about 8 to about 24 hours or about 4 to about 12 hours. Is defined. Such active agent release is measured by in-vitro elution of USP Apparatus 1 (basket) at 37 ° C. in 900 ml of simulated gastric fluid without enzyme (SGF) at 100 rpm. For example, the amount released 20% from the dosage form in 8 hours in-vitro, and the amount released 60% (± 12) from the dosage form in 24 hours is "20 in the elapsed time from about 8 to about 24 hours." Literally fits the definition of “proportional within%”. This is explained by the latter elapsed time (24 hours) and the latter release (60%) being the same multiple (3) of the former time (8 hours) and the former release (20%). To meet the definition of “proportional within 20% to an elapsed time of about 8 to about 24 hours” (or any other time), the definition may be proportional to other time points within the endpoint. This is not excluded, but it is only necessary to consider the end point of the numerical value.

  In another embodiment of the present invention, “substantially zero order release” is measured by in-vitro elution of USP Apparatus 1 (basket) at 37 ° C. in 900 ml simulated gastric fluid without enzyme (SGF) at 100 rpm. The amount of active agent released in 2 hours is less than about 25%, the amount of active agent released from the dosage form in 4 hours is from about 10% to about 30%, and from the dosage form in 8 hours. The amount of active agent released is about 20% to about 60%, the amount of active agent released from the dosage form in 12 hours is about 40% to about 90%, and released from the dosage form in 18 hours. Defined as a dosage form in which the amount of active agent is greater than about 70%.

  The term “polyethylene oxide” for the purposes of the present invention has a molecular weight of at least 25,000 daltons, preferably a molecular weight of at least 100,000, as measured conventionally in the art based on rheological measurements. Defined as a composition of polyethylene oxide (PEO) which is 000 daltons. Low molecular weight compositions are commonly referred to as polyethylene glycol (PEG).

  For the purposes of the present invention, the term “high molecular weight polyethylene oxide (PEO)” is defined as polyethylene oxide having an approximate molecular weight of at least 1,000,000 daltons based on rheological measurements.

  For the purposes of the present invention, “low molecular weight polyethylene oxide (PEO)” is defined as polyethylene oxide having an approximate molecular weight of less than 1,000,000 daltons based on rheological measurements.

  For the purposes of the present invention, the term “direct compression” refers to a process wherein the dosage form includes blending the ingredients and compressing the blend to form the dosage form, eg, diffusion blending and / or Alternatively, it is defined as referring to a process that is generated by using a convective mixing process (eg, Guidance for Industry, SUPAC-IR / MR: Immediate Release and Modified Release Solid Ordodum Education, Manufacturing Facility).

  “Planarization” and related terms, when used in the context of planarizing a dosage form according to the present invention, are substantially equivalent to the minimum diameter (ie, thickness) of the dosage form if the dosage form is other than spherical. When the shape of the dosage form is spherical, it means receiving a force applied from any direction.

  For the purposes of certain embodiments of the invention, the term “cannot be crushed” refers to a dosage form that can be at least planarized with a bench press as described herein without breaking. Is defined to refer to

  For the purposes of the present invention, the term “opioid analgesic” refers to opioid agonist bases, opioid agonist-antagonist mixtures, partial opioid agonists, pharmaceutically acceptable salts, complexes, stereoisomers, ethers, esters, It means one or more compounds selected from hydrates and their solvates and mixtures thereof.

  As used herein, the term “pseudogastric fluid” or “SGF” refers to an aqueous solution, such as a 0.1 N HCl solution, that is utilized in a dissolution test to mimic the state of the stomach.

  “Percentage point” is, for example, in the context of “the amount of active agent released from the leveling agent form in 0.5 hours does not deviate more than about 20 percentage points from the non-flattening agent form” It means that the difference between the% release before planarization and the% release after planarization does not exceed 20% (ie 20% or less). For example, 60% release from the planarizing form does not exceed about 20 percentage points from 40% release of the non-planarizing form.

  The use of the term “percentage” or “%”, not with respect to “percentage (or%) points”, means the usual percent. 40% is not literally within 20% of 60% release, for example, 48% release is equal to and within range of 20% of 60% release.

  The term “patient” refers to a subject (preferably a human) who exhibits clinical symptoms of a particular symptom (s) suggesting the need for treatment, a subject treated prophylactically or as a preventive measure for a disease state, Or a subject that has been diagnosed with a condition to be treated.

  The term “subject” includes the definition of the term “patient” and the term “healthy subject” that is completely normal in all respects or in terms of a particular disease state (ie, an individual (eg, a human) ) Is included.

  As used herein, the term “stereoisomer” is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. This includes optical isomers and isomers (diastereomers) of compounds where more than one chiral center is not a mirror image of one another.

  The term “chiral center” refers to a carbon atom to which four different groups are attached.

  The term “optical isomer” or “optical isomerism” refers to a molecule that is optically active because it is not superimposed on its mirror image, which rotates the plane of polarized light in one direction and its mirror image is the opposite. Rotate the plane of polarization in the direction.

  The term “racemic” refers to a mixture of optical isomers.

  The term “resolution” refers to the separation, concentration or removal of one of the two optically isomeric forms of a molecule.

  For the purposes of the present invention, “hydrocodone” includes hydrocodone free base, as well as pharmaceutically acceptable salts, complexes, stereoisomers, ethers, esters, hydrates and solvates thereof and mixtures thereof. Is defined as

  For the purposes of the present invention, “oxycodone” includes oxycodone free base and pharmaceutically acceptable salts, complexes, stereoisomers, ethers, esters, hydrates and solvates thereof and mixtures thereof. Is defined as

  For the purposes of the present invention, “naloxone” includes naloxone free base and pharmaceutically acceptable salts, complexes, stereoisomers, ethers, esters, hydrates and solvates thereof and mixtures thereof. Is defined as

  The term “USP Paddle or Basket method” is a Paddle and Basket method, for example, U.S. Pat. S. Pharmacopoeia XII (1990).

  For the purposes of the present invention, the term “pH-dependent” is defined as having a property (eg, dissolution) that varies with environmental pH.

  For the purposes of the present invention, the term “pH-independent” is defined as having a property (eg, dissolution) that is substantially unaffected by pH.

  For the purposes of the present invention, the term “bioavailability” is defined as the appropriate degree that a drug (eg, hydrocodone) is absorbed from a unit dosage form. Bioavailability is also referred to as AUC (ie, the area under the plasma concentration / time curve).

  For the purposes of the present invention, the terms “controlled release”, “release extended” or “sustained release” are interchangeable and have a blood (eg, plasma) concentration of at least about 12 hours or more, or It is defined as the release of a drug (eg, hydrocodone) at a rate such that it remains within the therapeutic range but below a toxic concentration over a period of at least 24 hours. Preferably, the controlled release dosage form can provide administration once a day or twice a day.

The term “C _max ” means the maximum plasma concentration obtained during the dosing interval.

The term “C ₂₄ ” as used herein is the plasma concentration of a drug 24 hours after administration.

The term “T _max ” means the time to maximum plasma concentration (C _max ).

For the purposes of the present invention, the term “C ₂₄ / C _max ratio” is defined as the ratio of the plasma concentration of the drug 24 hours after administration to the maximum plasma concentration obtained within the dosing interval.

The term “T _lag ” means the time point just before the first measurable plasma concentration.

“T _1/2 ” means plasma terminal half-life. This is the time it takes for any terminal phase concentration to be halved. The term “minimum effective analgesic concentration” or “MEAC” with respect to the concentration of opioids such as hydrocodone is extremely difficult to measure. However, there is generally a minimum effective analgesic concentration of plasma hydrocodone that does not result in pain relief. For example, there is an indirect relationship between plasma hydrocodone concentration and pain disappearance, but there is a relationship in which pain relief generally increases as plasma concentration increases and persists. There is a delay (or hysteresis) between the time of maximum plasma hydrocodone concentration and the time of maximum drug effect. This is generally true for the treatment of pain with opioid analgesics.

  For the purposes of the present invention, unless otherwise specified, the term “patient” or “subject” means that the discussion (or claim) is directed to the pharmacokinetic parameters of the individual patient or subject.

  The terms “patient population” or “subject population” or “healthy subject population” refer to at least two patients, subjects, or healthy subjects whose consideration (or claims) are at least patients, subjects or health. Is meant to cover the average pharmacokinetic parameters of 6 subjects, or at least 12 patients, subjects or healthy subjects.

In certain embodiments, the controlled release formulations disclosed herein are dose proportional. In dose proportional formulations, pharmacokinetic parameters (eg, AUC and C _max ) and / or in-vitro release increase linearly with dose titer. Thus, the pharmacokinetic and in-vitro parameters for a particular dose can be inferred from the different dose parameters of the same formulation.

  The term “first administration” refers to a single dose of the invention at the start of treatment for an individual subject, patient, or healthy subject or subject population, patient population, or healthy subject population.

  The term “steady state” means that the amount of drug reaching the system is approximately the same as the amount of drug leaving the system. Thus, in the “steady state”, the patient's body is removed at approximately the same rate that the drug becomes available to the patient's system through absorption into the bloodstream.

  In certain embodiments, the present invention is directed to a controlled release pharmaceutical formulation comprising an opioid antagonist inside the dosage form and an opioid antagonist outside the dosage form. In certain embodiments, the interior and exterior are configured as an inner core (eg, a compressed tablet) and a shell (eg, a compression coating) that encloses the core. In an alternative embodiment, the shell does not contain an antagonist and contains an antagonist only in the core. In preferred embodiments, at least a portion of the opioid antagonist is released into the colon to treat opioid-induced adverse pharmacodynamic responses (eg, constipation).

  In certain embodiments, a solid controlled release dosage form comprises a core comprising a first portion of an opioid antagonist and a shell enclosing the core and comprising a second portion of the opioid antagonist. In addition, the release characteristics of the first portion of the opioid antagonist are different from the release characteristics of the second opioid antagonist.

  In one embodiment, the release profile is defined as the amount of opioid antagonist released from the core and shell. For example, the amount of antagonist released from the core may be greater than the amount of antagonist released from the shell. Alternatively, the amount of antagonist released from the core may be less than the amount of antagonist released from the shell.

  In another embodiment, the release profile is defined as the release rate of the opioid antagonist. For example, the release rate of the antagonist in the core may be greater than the release rate of the antagonist in the shell. Alternatively, the release rate of the antagonist in the core may be less than the release rate of the antagonist in the shell.

  Further, in certain embodiments, the release profile is defined as the duration of release of the opioid antagonist. For example, the duration of antagonist release from the core may be longer than the duration of antagonist release from the shell. Alternatively, the duration of antagonist release from the core may be shorter than the duration of antagonist release from the shell. In certain embodiments, the shell provides immediate release of the antagonist and the core provides controlled release of the antagonist. In one embodiment, at least some of the antagonist in the core is not released until the dosage form enters the lower gastrointestinal tract (eg, colon).

  The first and second portions of the opioid antagonist are independently, for example, albimopan, amifenazole, cyclazocine, levalorphan, N-allyllevorphan, naltreson, methylnaltrexone, N-methylnaltrexone, naloxone, It can be selected from the group consisting of nalmefene, N-methylnalmefene, nadide, nalorphine, oxylorphan, pharmaceutically acceptable salts thereof and mixtures thereof. In certain embodiments, the antagonist is naloxone hydrochloride. In another embodiment, the antagonist is naltrexone hydrochloride.

  In one embodiment, the first portion of the opioid antagonist comprises the same agent as the second portion of the opioid antagonist. In other embodiments, the first portion of the opioid antagonist comprises a different agent than the second portion of the opioid antagonist. In certain embodiments, the first portion of the opioid antagonist and the second portion of the opioid antagonist both comprise naloxone or a pharmaceutically acceptable salt thereof.

  In one embodiment, the first portion of the opioid antagonist is an amount that prevents abuse of the dosage form. Abuse prevented can be, for example, intravenous abuse or nasal abuse.

  The dosage forms as disclosed herein may further comprise or be administered with an opioid analgesic. In such embodiments, the second portion of the opioid antagonist can be an amount that prevents opioid-induced adverse effects (eg, constipation). In certain embodiments, the antagonist in the core portion is at least partially released into the colon.

  In certain embodiments containing opioid analgesics, the dosage form of the present invention prevents modification by making it difficult to crush or grind (eg, according to the flattening criteria disclosed herein). This property makes it particularly suitable for controlled release opioid analgesic products having large doses of opioid analgesic to be released from each dosage unit over a period of time. Drug abusers typically obtain controlled release products and crush, shear, crush, chew, dissolve, heat, extract, or otherwise break the product, resulting in opioid analgesic Most or all contents are made available for immediate absorption by infusion, inhalation, and / or oral consumption.

  In certain embodiments, the shell of the dosage form of the present invention is difficult to physically separate from the core. This is particularly useful in embodiments where the amount of opioid analgesic in the core is increased compared to the shell, since abusers have difficulty reaching the larger drug payload in the core.

  In certain embodiments, the present invention provides a core comprising a first portion of an opioid antagonist dispersed in a first matrix material, the core enclosing the core and dispersed in a second matrix material. A solid controlled release dosage form comprising a shell comprising a shell portion of an opioid antagonist.

  The core of the dosage form can be formed, for example, by direct tableting, extrusion or molding. Preferably, the core comprises a controlled release excipient and is in the form of a compressed tablet.

  The dosage form shell can be formed, for example, by compression coating, molding, spraying one or more layers on the core, dipping one or more layers on the core, or a combination thereof. Preferably, the shell includes a controlled release excipient and is a compression coating.

  In preferred embodiments, the weight ratio of the core to the shell of the dosage forms described herein is from about 10: 1 to about 1:10; from about 5: 1 to about 1: 5; from about 2: 1 to about 1 :. 5; about 2: 1 to about 1: 2; about 1: 0.6 to about 1: 1.5; or about 1: 0.8 to about 1: 1.2.

In a preferred embodiment, the core and shell are not visually distinguishable from each other (eg, by color) and there is no clear boundary between the two components. This helps prevent modification of the dosage form by interfering with the effort to separate the core, and in certain embodiments contains a large amount of active agent. One measurement that can be used to evaluate shell and core colors is the CIEL ^* A ^* B ^* value. Preferably, the CIEL ^* A ^* B ^* values of the core and shell are within 10% of each other. Another measure of assessing color is the use of RYB or RGB hue circles, preferably with the core and shell matching the same hue or adjacent hues.

  In certain embodiments, the first matrix material in the shell comprises polyethylene oxide (PEO). In other embodiments, the second matrix material in the core comprises PEO. In yet another embodiment, both the first matrix material in the shell and the second matrix material in the core comprise PEO. Preferably, PEO is contained in both components. In such embodiments, the average molecular weight of PEO in the first matrix material is the same as or different from the average molecular weight of PEO in the second matrix material. In certain embodiments, the average molecular weight of the PEO contained in the core and shell is within 20%, within 10% or within 5% of each other.

  In a preferred embodiment of the invention, when PEO is present in both the first and second matrices, the average molecular weight of the PEO used for the first matrix in the core is the second matrix material in the shell. Less than the average molecular weight of the PEO used. For example, the PEO in the first matrix material can have an average molecular weight of about 300,000 daltons to about 10,000,000 daltons, and the PEO in the second matrix material can have an average molecular weight of about 1,000,000. 000 Daltons to about 10,000,000 Daltons. In other embodiments, the PEO in the first matrix material can have an average molecular weight of about 300,000 daltons to about 3,000,000 daltons, and the PEO in the second matrix material has an average molecular weight of about From 4,000,000 daltons to about 10,000,000 daltons. In other embodiments, the PEO in the first matrix material can have an average molecular weight of about 500,000 daltons to about 1,000,000 daltons, and the PEO in the second matrix material has an average molecular weight of about It can be from 6,000,000 daltons to about 8,000,000 daltons.

  In certain embodiments, the opioid antagonist in the core portion is the same as the opioid antagonist in the shell portion. In other embodiments, the opioid antagonist in the core portion is different from the opioid antagonist in the shell portion.

  In certain embodiments containing an opioid analgesic, the weight ratio of the opioid analgesic in the core to the ratio of opioid analgesic in the shell is about 1: 1 to about 10: 1; about 2: 1 to about 8 : 1; about 2: 1 to about 5: 1 or about 4: 1.

  In certain embodiments, the weight ratio of the first portion of opioid analgesic in the core to PEO in the first matrix material is about 4: 1 to about 1:30; about 2: 1 to about 1: 100; about 2: 1 to about 1:20; about 1: 1 to about 1:10; about 1:15 to about 1:20; about 1:15 to about 1: 4; or about 1: 2.

  In another embodiment, the weight ratio of the second portion of opioid analgesic in the shell to PEO in the second matrix material is from about 1: 1 to about 1: 200; from about 1: 1 to about 1: 125. About 1: 2 to about 1: 100; about 1: 5 to about 1:50; about 1:12 to about 1:25, about 1:98, or about 1:15.

  In certain embodiments containing an opioid analgesic, the agent is measured by in-vitro elution of USP Apparatus 1 (basket) at 37 ° C. in 900 ml simulated gastric fluid without enzyme (SGF) at 100 rpm. The amount of opioid analgesic released from the form is proportional within 20%, or within 10%, or within 5% of the elapsed time 8-24 hours.

  In certain embodiments containing an opioid analgesic, the agent is measured by in-vitro elution of USP Apparatus 1 (basket) at 37 ° C. in 900 ml simulated gastric fluid without enzyme (SGF) at 100 rpm. The amount of opioid analgesic released from the form is proportional within 20%, or within 10%, or within 5% of the elapsed time 8-18 hours.

  In certain embodiments containing an opioid analgesic, the agent is measured by in-vitro elution of USP Apparatus 1 (basket) at 37 ° C. in 900 ml simulated gastric fluid without enzyme (SGF) at 100 rpm. Contains opioid analgesic, wherein the amount of opioid analgesic released from the form is proportional within 20%, or within 10%, or within 5% of the elapsed time of 8-12 hours.

  In certain embodiments containing an opioid analgesic, the agent is measured by in-vitro elution of USP Apparatus 1 (basket) at 37 ° C. in 900 ml simulated gastric fluid without enzyme (SGF) at 100 rpm. The amount of opioid analgesic released from the form is proportional within 20%, or within 10%, or within 5% of the elapsed time 12-24 hours.

  In certain embodiments containing an opioid analgesic, the agent is measured by in-vitro elution of USP Apparatus 1 (basket) at 37 ° C. in 900 ml simulated gastric fluid without enzyme (SGF) at 100 rpm. The amount of opioid analgesic released from the form is proportional within 20%, or within 10%, or within 5% of the elapsed time 12-18 hours.

  In certain embodiments containing an opioid analgesic, the agent is measured by in-vitro elution of USP Apparatus 1 (basket) at 37 ° C. in 900 ml simulated gastric fluid without enzyme (SGF) at 100 rpm. The amount of opioid analgesic released from the form is proportional within 20%, or within 10%, or within 5% of the elapsed time 4-20 hours.

  In certain embodiments containing an opioid analgesic, the agent is measured by in-vitro elution of USP Apparatus 1 (basket) at 37 ° C. in 900 ml simulated gastric fluid without enzyme (SGF) at 100 rpm. The amount of opioid analgesic released from the form is proportional to within 20%, or within 10%, or within 5% of the elapsed time 4-15 hours.

  In certain embodiments containing an opioid analgesic, the agent is measured by in-vitro elution of USP Apparatus 1 (basket) at 37 ° C. in 900 ml simulated gastric fluid without enzyme (SGF) at 100 rpm. The amount of opioid analgesic released from the form is proportional within 20%, or within 10%, or within 5% of the elapsed time of 4-10 hours.

  In certain embodiments containing an opioid analgesic, the agent is measured by in-vitro elution of USP Apparatus 1 (basket) at 37 ° C. in 900 ml simulated gastric fluid without enzyme (SGF) at 100 rpm. The amount of opioid analgesic released from the form is proportional within 20%, or within 10%, or within 5% of the elapsed time 8-20 hours.

  In certain embodiments containing an opioid analgesic, the agent is measured by in-vitro elution of USP Apparatus 1 (basket) at 37 ° C. in 900 ml simulated gastric fluid without enzyme (SGF) at 100 rpm. The amount of opioid analgesic released from the form is proportional within 20%, or within 10%, or within 5% of the elapsed time 10-15 hours.

  In certain embodiments containing opioid analgesics, in-vitro elution of USP Apparatus 1 (basket) at 37 ° C. in 900 ml simulated gastric fluid without enzyme (SGF) measured at 100 rpm. The amount of opioid analgesic released over time (by weight) is about 25%; the amount of opioid released from the dosage form in 4 hours is from about 10% to about 30%; from the dosage form in 8 hours The amount of opioid released is about 20% to about 60%; the amount of opioid released from the dosage form in about 12 hours is about 40% to about 90%; and the opioid released from the dosage form in 18 hours Is greater than about 70%.

  In certain embodiments containing opioid analgesics, in-vitro elution of USP Apparatus 1 (basket) at 37 ° C. in 900 ml simulated gastric fluid without enzyme (SGF) measured at 100 rpm. The amount of opioid analgesic released over time (by weight) is about 15%; the amount of opioid released from the dosage form in 4 hours is about 10% to about 20%; from the dosage form in 8 hours The amount of opioid released is about 30% to about 45%; the amount of opioid released from the dosage form in about 12 hours is about 50% to about 70%; and the opioid released from the dosage form in 18 hours Is greater than about 90%.

  In certain embodiments containing opioid analgesics, in-vitro elution of USP Apparatus 1 (basket) at 37 ° C. in 900 ml simulated gastric fluid without enzyme (SGF) measured at 100 rpm. The amount of opioid analgesic released by time (by weight) is about 10%; the amount of opioid released from the dosage form by 4 hours is about 20% to about 30%; from the dosage form by 8 hours The amount of opioid released is about 45% to about 60%; the amount of opioid released from the dosage form in about 12 hours is about 70% to about 90%; and the opioid released from the dosage form in 18 hours Is greater than about 95%.

  In certain embodiments containing an opioid analgesic, the agent is measured by in-vitro elution of USP Apparatus 1 (basket) at 37 ° C. in 900 ml simulated gastric fluid without enzyme (SGF) at 100 rpm. The amount (by weight) of the opioid analgesic released from the form is proportional to within 20% of the elapsed time 8-24 hours, showing at least one of the following: (i) of the opioid analgesic released in 2 hours (Ii) the amount of opioid analgesic released in 4 hours is from about 10% to about 30%; (iii) the amount of opioid analgesic released in 8 hours is about 30; % To about 60%, (iv) the amount of opioid analgesic released in 12 hours is from about 50% to about 90%, or (v) opioid released in 18 hours The amount of analgesic agent is about 80%.

  In certain embodiments containing an opioid analgesic, the agent is measured by in-vitro elution of USP Apparatus 1 (basket) at 37 ° C. in 900 ml simulated gastric fluid without enzyme (SGF) at 100 rpm. The amount (by weight) of the opioid analgesic released from the form is proportional to within 20% of the elapsed time 8-24 hours, showing at least one of the following: (i) of the opioid analgesic released in 2 hours (Ii) the amount of opioid analgesic released in 4 hours is about 10% to about 20%, and (iii) the amount of opioid analgesic released in 8 hours is about 30. % To about 45%, (iv) the amount of opioid analgesic released in 12 hours is about 50% to about 70%, or (v) opioid released in 18 hours The amount of analgesic agent is about 90%.

  In certain embodiments containing an opioid analgesic, the agent is measured by in-vitro elution of USP Apparatus 1 (basket) at 37 ° C. in 900 ml simulated gastric fluid without enzyme (SGF) at 100 rpm. The amount (by weight) of the opioid analgesic released from the form is proportional to within 20% of the elapsed time 8-24 hours, showing at least one of the following: (i) of the opioid analgesic released in 2 hours (Ii) the amount of opioid analgesic released in 4 hours is about 20% to about 30%; (iii) the amount of opioid analgesic released in 8 hours is about 45%; % To about 60%, (iv) the amount of opioid analgesic released in 12 hours is from about 70% to about 90%, or (v) opioid released in 18 hours The amount of analgesic agent is about 95%.

  In certain embodiments containing an opioid analgesic, the agent is measured by in-vitro elution of USP Apparatus 1 (basket) at 37 ° C. in 900 ml simulated gastric fluid without enzyme (SGF) at 100 rpm. The amount (by weight) of the opioid analgesic released from the form is proportional to within 20% of the elapsed time 8-24 hours, showing at least one of the following: (i) of the opioid analgesic released in 2 hours Less than about 15%; (ii) the amount of opioid analgesic released in 4 hours is about 8% to about 20%; and (iii) the amount of opioid analgesic released in 8 hours is about 20%. % To about 50%, and (iv) the amount of opioid analgesic released in 12 hours is about 40% to about 70%, and (v) opioid analgesic released in 18 hours. The amount is about 70% or more, or (vi) the amount of released opioid analgesics in 24 hours is about 90%.

Dosage form

In certain embodiments, the core is dry mixed with the controlled release matrix material, the opioid antagonist, any opioid agonist and any of the various excipients, followed by mixing until a suitable granulation is obtained. It can be prepared by granulation. The process can be performed by a dry or wet granulation method. Typically in wet granulation, wet granules are dried in a fluid bed dryer, sieved and ground to a suitable size. Typically, a lubricant is mixed with the granulation to obtain the final core formulation.

  Pharmaceutical compositions of the present invention include, but are not limited to, single unit dosage forms suitable for oral administration such as tablets, capsules, gelcaps, and caplets, which are compatible with controlled or immediate release. it can.

  In some embodiments, the controlled release component can include gels, dialysis membranes, osmotic systems, multilayer coatings, microparticles, multiparticles, liposomes, microspheres, or combinations thereof, with varying ratios as desired. Release characteristics can be provided.

  A non-limiting list of suitable controlled release matrix materials that can be selected for inclusion in formulations according to the present invention include sustained release polymers, rubbers, acrylics, protein derived materials, waxes, shellacs, and Examples include hydrophilic and hydrophobic materials such as oils such as hydrogenated castor oil and hydrogenated vegetable oil. More specifically, controlled release materials include, for example, polyalkylene oxides such as polyethylene oxide (PEO), alkyl celluloses such as ethyl cellulose, acrylic and methacrylic acid polymers and copolymers, and hydroxyalkyl celluloses (eg, hydroxypropyl methylcellulose, HPMC) and cellulose ethers such as carboxyalkyl cellulose. Waxes include, for example, natural and synthetic waxes, fatty acids, fatty alcohols, and mixtures thereof (eg, beeswax, carnauba wax, stearic acid and stearyl alcohol). In certain embodiments, a mixture of two or more controlled release materials is used in the core matrix. However, any pharmaceutically acceptable hydrophobic or hydrophilic controlled release material that can provide controlled release of the active agent can be used in accordance with the present invention.

  In other embodiments, the controlled release polymer includes methyl methacrylate, methyl methacrylate copolymer, ethoxyethyl methacrylate, ethyl acrylate, trimethylammonioethyl methacrylate, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly (acrylic acid), poly (methacrylic acid). Acid), alkyl amine methacrylate copolymers, methacrylic acid and ethyl acrylate copolymers, vinyl acetate and vinyl pyrrolidone copolymers, vinyl acetate and crotonic acid copolymers, polymethyl vinyl ether and malonic anhydride copolymers, polymethyl vinyl ether and malonic acid or ethyl-, isopropyl -, N-butyl ester copolymer, poly (methyl methacrylate), poly (meta Rilic acid) (anhydride), polymethacrylate, polyacrylamide, poly (methacrylic anhydride), acetyl succinate, polyvinyl acetate, polyvinyl acetate phthalate, polyvinyl pyrrolidone, polyacrylic acid, polysaccharide, modified starch, cross-linked high amylose Starch, hydroxypropyl starch, starch, hydroxypropylmethylcellulose phthalate, microcrystalline cellulose, carboxymethylethylcellulose, cellulose acetate, methylcellulose, ethylcellulose, hydroxypropylcellulose, cellulose phthalate, cellulose acetate, cellulose acetate phthalate, cellulose acetate propionate, cellulose acetate Succinate, cellulose acetate butyrate, cell Over scan acetate trimellitate, poloxamer, povidone, alginic acid, sodium alginate, polyethylene glycol alginate, xanthan gum, polymethacrylates, can be cited zein, and glycidyl methacrylate copolymers. In certain preferred embodiments, any sustained release material mixture is used in the matrix of the present invention.

  The core may also contain suitable amounts of excipients such as lubricants, binders, granulating aids, diluents, colorants, flavoring agents (eg stimulants or bittering agents) and lubricants. All of which are common in the art.

  Specific examples of pharmaceutically acceptable diluents and excipients that can be used to formulate the core are described in Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (1986) and are described herein with respect to this disclosure. Incorporated by reference.

  In preferred embodiments, the dosage form matrix of the present invention incorporates PEO (eg, high and / or low molecular weight PEO).

  A 2% (by weight) aqueous solution of PEO was added to a Brookfield viscometer Model RVF, spindle no. 1 shows a viscosity range of 400-800 mPa-s (cP) at 25 rpm and 10 rpm, the PEO is considered to have an average molecular weight of 1,000,000 daltons.

  A 2% (by weight) aqueous solution of PEO was added to a Brookfield viscometer Model RVF, spindle no. 3 shows a viscosity range of 2000-4000 mPa-s (cP) at 10 rpm and 25 ° C., PEO is considered to have an average molecular weight of 2,000,000 daltons.

  A 1% (by weight) aqueous solution of PEO was added to a Brookfield viscometer Model RVF, spindle no. PEO is considered to have an average molecular weight of 4,000,000 daltons when it shows a viscosity range of 1650 to less than 5500 m Pa-s (cP) at 25 rpm and 2 rpm.

  A 1% (by weight) aqueous solution of PEO was added to a Brookfield viscometer Model RVF, spindle no. 2 shows a viscosity range of 5500-7500 m Pa-s (cP) at 2 rpm and 25 ° C., PEO is considered to have an average molecular weight of 5,000,000 daltons.

  A 1% (by weight) aqueous solution of PEO was added to a Brookfield viscometer Model RVF, spindle no. PEO is considered to have an average molecular weight of 7,000,000 daltons when using 2 to show a viscosity range of less than 7500-10,000 m Pa-s (cP) at 2 rpm and 25 ° C.

  A 1% (by weight) aqueous solution of PEO was added to a Brookfield viscometer Model RVF, spindle no. 2 shows a viscosity range of 10,000-15,000 mPa-s (cP) at 2 rpm and 25 ° C., PEO is considered to have an average molecular weight of 8,000,000 daltons.

  For low molecular weight PEO, a 5% (by weight) aqueous solution of polyethylene oxide was added to a Brookfield viscometer Model RVT, spindle no. 1 shows a viscosity range of 30-50 mPa-s (cP) at 50 rpm at 25 ° C., PEO is considered to have an average molecular weight of 100,000 Daltons.

  A 5% (by weight) aqueous solution of PEO was added to a Brookfield viscometer Model RVF, spindle no. 2 shows a viscosity range of 8800-17,600 mPa-s (cP) at 25 rpm at 2 rpm, the polyethylene oxide is considered to have an average molecular weight of 900,000 daltons.

Compressed Coating Dosage Form In embodiments where a compression coating is used to make the shell, all or part of the pharmaceutically acceptable excipient (s) in the coating provides sufficient compressibility and the formulation It is preferable to provide a product that is commercially acceptable. Compressive coating of the shell onto the preformed core depends in part on the specific properties of the selected excipient and active agent, for example, in terms of polymer solubility, fluidity, glass transition temperature, etc. doing.

  In a non-limiting embodiment, the compression coating dosage form can be prepared, for example, by using a pre-made core prior to coating, or by preparing the core (eg, by compression). The inner core is granulated by wet or dry granulation of opioid antagonists (with or without opioid agonists) with pharmaceutically acceptable excipients, followed by drying and grinding as necessary And optionally adding a particulate excipient and / or an opioid antagonist or optionally an opioid agonist, if necessary, adding a lubricant and mixing the granulate with a tablet machine. It can be prepared by compression. The resulting compressed core can optionally be coated with a functional coating or film coating prior to compression coating.

  Formulations for shell compression coatings can be prepared by substantially the same process as core formulations using any of the controlled release materials disclosed above. Preferably the compression coating comprises PEO. The formulation can be coated onto the core by compression. The core and / or coating may be compressed using, for example, a Killion or Fette rotary press with a compression force of about 1 to about 20 kilo-Newtons.

  In certain embodiments, a Manesty Dry-Cota press (eg, Model 900) can be used. This device consists of two tablet presses connected in parallel, the core is made on one press and then mechanically transferred to the next press for compression coating. Each press has an independent powder feed mechanism so that the core formulation is placed on one machine and the coating formulation is placed on the other machine. A mechanical transfer arm rotates between the machines to remove the core from the core press and move it to the coating press. Other presses that can be used to prepare the dosage forms of the present invention include Elizabeth HataHT-AP44-MSU-C, Killian RLUD, and Fette PT4090, each for coating formulations and prefabricated cores. Has a dual supply system. With these presses, multiple compression coating layers can be realized by reusing already compression coated tablets. All of these presses have a mechanism for placing the tablets in the vertical and radial centers in the coating formulation.

  In certain embodiments, the shell is not applied at the same thickness all around the core, but instead is applied at a different thickness around the inner core. The thin part of the coating creates the part of the dosage form that releases the drug from the core faster than the other part. This can be easily achieved, for example, by ensuring that the core to which the shell is applied is not in the center of the press during coating.

  In certain embodiments, the shell can be further overcoated with a hydrophobic or enteric coating material. In other embodiments, the shell can be coated with a hydrophilic coating in addition to or instead of a hydrophobic or enteric coating.

  In further embodiments, a coat (eg, hydrophobic, hydrophilic or enteric) can optionally be applied instead or additionally as an intermediate layer between the core and shell.

Active Agents In addition to opioid antagonists, certain embodiments include opioid analgesics in the core, shell, or both components. Opioid analgesics useful in the present invention include alfentanil, allylprozin, alphaprozin, anilellidine, benzylmorphine, vegitramide, buprenorphine, butorphanol, clonitazen, codeine, desomorphin, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine , Dihydromorphine, dimenoxadol, dimefeptanol, dimethylthiambutene, dioxafetil butyrate, dipipanone, eptazocine, etoheptadine, ethylmethylthiambutene, ethylmorphine, etnitazene, etorphine, dihydroethorphine, fentanyl and derivatives, Hydrocodone, hydromorphone, hydroxypetidine, isomethadone, ketobemidone, levorphanol, le Phenacylmorphane, lofentanil, meperidine, meptazinol, metazocine, methadone, methopone, morphine, mylofin, narcein, nicomorphine, norlevorphanol, normethadone, nalolphine, nalbufen, normorphin, norpipanone, opium, oxycodone, oxymorphone, papaveretam , Pentazocine, phenadoxone, phenomorphan, phenazosin, phenoperidine, pimidine, pyritramide, profeptadine, promedol, properidine, propoxyphene, sufentanil, thyridine, tramadol, pharmaceutically acceptable salts, complexes (e.g., cyclodextrin and ), Stereoisomers, ethers, esters, hydrates, solvates, derivatives and mixtures thereof. But it is not limited to.

  Preferably, the opioid analgesic is codeine, hydrocodone, hydromorphone, morphine, oxycodone, oxymorphone, tramadol, a pharmaceutically acceptable salt, complex, stereoisomer, ether, ester, hydrate, solvate, Selected from the group consisting of these derivatives and mixtures.

  In certain embodiments, the opioid analgesic is selected from the group consisting of hydrocodone, pharmaceutically acceptable salts, derivatives and mixtures thereof. In one embodiment, the opioid analgesic is hydrocodone hydrogen tartrate.

  In other embodiments, the opioid analgesic is selected from the group consisting of oxycodone, pharmaceutically acceptable salts, derivatives and mixtures thereof. In one embodiment, the opioid analgesic is oxycodone hydrochloride.

  Opioid antagonists or agonists used in accordance with the present invention may contain one or more asymmetric centers and may give rise to optical isomers, diastereomers, or other stereoisomeric forms. The present invention is meant to encompass all such possible forms as well as their racemic and resolved forms and the use of these compositions. Where the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, it is intended to include both E and Z geometric isomers. It is intended that the present invention encompasses all tautomeric forms.

  Pharmaceutically acceptable salts include inorganic acid salts such as hydrochloride, hydrogenate, sulfate and phosphate, organic acid salts such as formate, acetate, trifluoroacetate, maleate and tartrate. Sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate; amino acid salts such as alginate, aspartate, glutamate, metal salts such as sodium salt, potassium salt, cesium salt, calcium salt, magnesium salt, etc. Alkaline earth metals; and organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, or N, N′-dibenzylethylenediamine salt. It is not limited.

  In certain embodiments, the formulations disclosed herein can be utilized to deliver an active agent other than an opioid antagonist to the patient's colon. The drug can be a peptide that tends to degrade in the stomach and / or small intestine. Drugs include diabetes, osteoporosis, neurodegenerative disease, endometrial growth, acromegaly, diabetes insipidus, colon cancer, ulcerative colitis, immune disorder, inflammatory bowel disease, Crohn's disease, irritable bowel syndrome It can be a therapeutic agent for treatment. Specific classes of drugs include antitumor drugs, antibiotics, polypeptides, anti-inflammatory drugs, chemotherapeutic drugs, immunosuppressants, steroid drugs, vitamins, laxatives, polynucleotides or lactobacillus pharmaceutical formulations.

  Specific examples of drugs include human insulin, peptides with human insulin-like action, thyroid hormone (PTH), peptides with PTH-like action, human calcitonin, peptides with human calcitonin-like action, thyroid-releasing hormone (TRH) , Tartyrelin hydrate, luteinizing hormone releasing hormone (LH-RH), goserelin acetate, buserelin acetate, nafarelin acetate, oxytocin, human pituitary gonadotropin, octreotide acetate, somatropin, human chorionic gonadotropin, desmopressin acetate Salt, 5-fluorouracil, bleomycin, doxyfluridine, tegafur, tegafur 5-aminosalicylic acid, salazosulfapyridine, infliximab, budesonide, fluticasone propionate, beclomethasone propio Acid ester, dexamethasone, dexamethasone acetate, dexamethasone palmitate, dexamethasone sodium metasulfobenzoate, dexamethasone sodium phosphate, triamcinolone, triamcinolone acetonide, hydrocortisone, hydrocortisone sodium oxalate, fludrocortisone acetate, prednisolone, Prednisolone sodium succinate, prednisolone sodium phosphate, beclomethasone propionate, betamethasone, betamethasone d-chlorpheniramine maleic acid, betamethasone acetate, betamethasone sodium phosphate, betamethasone sodium phosphate, methylprednisolone, methylprednisolone sodium Succinate or methylprednisolone acetic acid And the like.

  In further embodiments, the dose can further comprise a non-opioid drug. Such non-opioid drugs include aspirin, acetaminophen; non-steroidal anti-inflammatory drugs (“NSAIDS”), such as ibuprofen, ketoprofen, etc .; N-methyl-D-aspartate (NMDA) receptor antagonists, such as , Dextromethorphan or dextrorphan, or ketamine; morphinans such as cyclooxygenase-II inhibitors (“COX-II inhibitors”); and / or glycine receptor antagonists.

  In certain embodiments of the invention that include opioid analgesics, the present invention further allows the use of low dose opioid analgesics by including non-opioid analgesics. By using low amounts of opioid analgesics, adverse effects associated with human opioids are also reduced.

  Suitable non-steroidal anti-inflammatory agents include ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, fulbufen, ketoprofen, indoprofen, pyroprofen, carprofen, oxaprozin, pranoprofen (pramoprofen). ), Muroprofen, trioxaprofen, suprofen, aminoprofen, thiaprofenic acid, fluprofen, bucuroxy acid, indomethacin, sulindac, tolmetine, zomepilac, thiopinac, zidonetacin, acemetacin, fenthiazac, clidanac, oxpinac (oxpinac) , Mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diphf Risaru, including flufenisal, piroxicam, sudoxicam or isoxicam, etc., and all of these pharmaceutically acceptable salts. Useful doses of these agents are well known to those skilled in the art.

N-methyl-D-aspartate (NMDA) receptor antagonists are well known in the art and include, for example, dextromethorphan or dextrorphan, morphinans such as ketamine, or pharmaceutically acceptable salts thereof. Is included. For the purposes of the present invention, the term “NMDA antagonist” refers to an agent that inhibits the main intracellular consequences of NMDA-receptor action, for example gangliosides such as GM ₁ or GT _1b , trifluoperazine such as phenothiazine or It includes naphthalenesulfonamides such as N- (6-aminohexyl) -5-chloro-1-naphthalenesulfonamide.

  The COX-II inhibitor can be selected from the group consisting of celecoxib, rofecoxib, valdecoxib, parecoxib, luminacoxib, etlicoxib, filocoxib, flosside, meloxicam, nabumetone, nimesulide and their pharmaceutically acceptable salts. Furthermore, embodiments can include non-opioid drugs that provide a desired effect other than pain relief, such as antitussives, expectorants, nasal congestion, antihistamines, local anesthetics, and the like.

Antagonist Formulations In certain embodiments of the invention, the total amount of (eg, naloxone or a pharmaceutically acceptable salt thereof or naltrexone or a pharmaceutically acceptable salt thereof) is, for example, from about 0.01 mg to about It can be 100 mg, about 0.1 mg to about 50 mg, about 0.1 mg to about 25 mg, about 0.5 mg to about 15 mg, or about 1 mg to about 12 mg.

  The amount of antagonist contained in the shell (eg, naloxone or a pharmaceutically acceptable salt thereof or naltrexone or a pharmaceutically acceptable salt thereof) is preferably where the dosage form also contains an opioid analgesic An amount that prevents intravenous or nasal abuse. In such embodiments, naloxone or a pharmaceutically acceptable salt thereof is, for example, in an amount of about 0.1 mg to about 5 mg, about 0.5 mg to about 1 mg, about 0.5 mg, or about 0.85 mg. Can exist.

  The amount of antagonist contained in the core is preferably an amount that treats opioid-induced deleterious pharmacodynamic effects such as constipation. In such embodiments, naloxone or a pharmaceutically acceptable salt thereof is, for example, in an amount of about 0.1 mg to about 5 mg, about 0.5 mg to about 1 mg, about 0.5 mg to about 0.85 mg. Can exist.

Oxycodone / Antagonist Embodiments In addition to the opioid antagonist, the controlled release oral dosage form of the present invention comprises, for example, from about 2.5 mg to about 320 mg of oxycodone or an equivalent amount of a pharmaceutically acceptable salt thereof. Can do. In other embodiments, the dosage form contains from about 5 mg to about 240 mg oxycodone or an equivalent thereof of a pharmaceutically acceptable salt, or from about 5 mg to about 120 mg of oxycodone or an equivalent of a pharmaceutically acceptable salt thereof. To do. In certain embodiments, the opioid agonist is, for example, oxycodone in an amount of about 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 60 mg, 80 mg, 120 mg, 160 mg or 320 mg. Its pharmaceutically acceptable salt (eg oxycodone hydrochloride).

In certain embodiments of the invention, when the active agent is oxycodone hydrochloride, the oxycodone hydrochloride is less than about 25 ppm, less than about 15 ppm, less than about 10 ppm, less than about 5 ppm, less than about 2 ppm, less than about 1 ppm, about 0.1 ppm. It has a 14-hydroxycodeinone concentration that is less than 5 ppm or less than about 0.25 ppm.
WO 2005/097801 A1, U.S. Pat. S. Pat. No. 7,129,248B2 and US2006 / 0173029A1. These are all incorporated herein by reference and describe a process for preparing oxycodone hydrochloride with reduced concentrations of 14-hydroxycodeinone.

Hydrocodone / Antagonist Embodiments In addition to the opioid antagonist, the controlled release oral dosage form of the present invention comprises, for example, from about 0.5 mg to about 1250 mg of hydrocodone or an equivalent amount of a pharmaceutically acceptable salt thereof. Can do. In other embodiments, the dosage form contains from about 2 mg to about 200 mg of hydrocodone or equivalent of a pharmaceutically acceptable salt thereof, or from about 16 mg to about 120 mg of hydrocodone or equivalent of a pharmaceutically acceptable salt thereof. To do. In certain preferred embodiments, the dosage form contains about 20 mg, about 30 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg or about 120 mg hydrocodone bitartrate.

  Suitable pharmaceutically acceptable salts of hydrocodone include hydrocodone tartrate, hydrocodone hydrogen tartrate hydrate, hydrocodone hydrochloride, hydrocodone p-toluenesulfonate, hydrocodone phosphate, hydrocodone thiosemicarbazone, hydrocodone sulfate. Salt, hydrocodone trifluoroacetate, hydrocodone 25 hydrate, hydrocodone pentafluoropropionate, hydrocodone p-nitrophenylhydrazone, hydrocodone o-methyl oxime, hydrocodone semicarbazone, hydrocodone hydroacid salt, hydrocodone mucin acid Salt, hydrocodone oleate, dihydrocodone phosphate, hydrocodone primary phosphate, inorganic hydrocodone salt, organic hydrocodone salt, hydrocodone acetate trihydrate, hydrocodone bis (heptafluorobutyrate) G), hydrocodone bis (methyl carbamate), hydrocodone bis (pentafluoropropionate), hydrocodone bis (pyridinecarboxylate), hydrocodone bis (trifluoroacetate), hydrocodone hydrochloride, and hydrocodone sulfate 5 water Japanese products are listed. Preferably, hydrocodone is present as tartrate.

In a preferred embodiment, hydrocodone formulations of the present invention is suitable for administration once daily, resulted in a relatively flat plasma profile, after which the plasma concentration of hydrocodone administered, C _{24 /} C _max ratio of from about 0. Is meant to provide 55 to about 1.0. In certain embodiments, the C ₂₄ / C _max ratio is from about 0.55 to about 0.85, from about 0.55 to about 0.75, or about 0.005 after administration of a single dose of the dosage form or at steady state. 60 to about 0.70. Other embodiments are suitable for twice daily administration.

In a preferred embodiment, the hydrocodone formulations of the invention provide a hydrocodone T _max (time) of about 4 to about 20 hours after administration. In certain embodiments, after administration of the dosage form, the T _max is about 6 to about 12 hours, about 8 to about 10 hours, about 4 to about 10 hours, about 8 to about 14 hours, or about 14 to about 20 It's time.

  In still other embodiments, the solid controlled release dosage form of the present invention is about 200-450 or about 250-400 per 20 mg hydrocodone or pharmaceutically acceptable salt thereof included in the dosage form after administration. This results in AUC (ng * h / mL).

  In certain embodiments, a solid controlled release dosage form containing 20 mg of hydrocodone or a pharmaceutically acceptable salt thereof is about 200 to about 450, about 250 to about 400, about 275 to about after administration. This results in an AUC (ng * h / mL) of 350, about 300-330 or about 280-about 320.

  In certain embodiments, a solid controlled release dosage form containing 120 mg of hydrocodone or a pharmaceutically acceptable salt thereof is about 1000 to about 3000, about 1500 to about 2400, about 1700 to about 1700 after administration. 2200, about 1800 to about 2100 or about 1900 to about 2100 AUC (ng * h / mL).

In other embodiments, the solid controlled release dosage form of the present invention provides a C _max (ng / mL) of about 5 to about 40, about 10 to about 30 per 20 mg of hydrocodone included in the dosage form after administration. Bring.

In certain embodiments, a solid controlled release dosage form containing 20 mg of hydrocodone or a pharmaceutically acceptable salt thereof is about 5 to about 40, about 10 to about 30, about 12 to about after administration. Resulting in a C _max (ng / mL) of 25, about 14 to about 18 or about 12 to about 17.

In certain embodiments, a solid controlled release dosage form containing 120 mg of hydrocodone or a pharmaceutically acceptable salt thereof is about 30 to about 120, about 60 to about 180, about 100 to about 180 after administration. Resulting in a C _max (ng / mL) of 160, about 110 to about 150, or about 100 to about 140.

In certain embodiments, the solid controlled release dosage form of the present invention is about 7 to about 22, about 10 to about 20, about 12 to about 18, about 13 to about 17, or about 14 to about after administration. This results in a T _max (time) of 16 hydrocodones.

In other embodiments, the solid controlled release dosage form of the invention provides a T _1/2 (time) of hydrocodone of about 5 to about 10; about 6 to about 9 or about 7 to about 8 after administration. .

In other embodiments, the solid controlled release dosage form of the present invention is about 0.01 to about 0.2; about 0.1 to about 0.18; about 0.3 to about 0.17 after administration. Or a T _lag (time) of hydrocodone of about 0.06 to about 0.15.

In other embodiments, the solid controlled release dosage form of the invention has about 0.2 to about 0.8; about 0.3 to about 0.7; or about 0.4 to about 0.6 hydrocodone. _{Resulting in} a C ₂₄ / C _max ratio of

  In certain embodiments, the in vivo parameter is an average value. In other embodiments, the in vivo parameters are achieved in a fasted state after administration.

In certain embodiments, after administration, the mean AUC (ng ^* h / mL) of the fed hydrocodone is less than 20% higher than the AUC (ng ^* h / mL) of the same dose hydrocodone after administration. Less than 16% or less than 12%.

In certain embodiments, after administration, the mean C _max (ng / mL) of foraged hydrocodone is less than 80%, less than 70% greater than the C _{max of} fasted hydrocodone after administration of the same dose of hydrocodone. High or less than 60% higher.

In certain embodiments, after administration, the mean T _max (time) of foraged hydrocodone is within 25% within 20% or within 15% of the fasted hydrocodone T _max after administration of the same dose of hydrocodone. is there.

In certain embodiments, after administration, the mean T _1/2 (time) of foraged hydrocodone is within 8% within 5% of the T _1/2 of fasted hydrocodone after administration of the same dose of hydrocodone, or Within 2%.

In certain embodiments, after administration, the mean T _lag of the fed hydrocodone is less than 150%, less than 125% higher or 100% higher than the T _1/2 of the fasted hydrocodone after administration of the same dose of hydrocodone. Less than%.

  In certain embodiments, any one or all of the above in vivo parameters are administered to a human subject, a patient or a healthy subject (individual data), or a population of human subjects, patients or healthy subjects (average data). Achieved after the first administration of the form.

  In certain other embodiments, any one or all of the above in vivo parameters are administered at a steady state of the dosage form to a human subject, patient or healthy subject, or population of human subjects, patient or healthy subject. Achieved.

Cured formulation In certain embodiments, the process of the present invention further comprises curing the final dosage form.

  In embodiments that include polyethylene oxide in the controlled release formulation, the curing step can include at least partially melting the polyethylene oxide in the formulation. In certain embodiments, at least about 20% or at least about 30% of the polyethylene oxide in the formulation melts. Preferably, during the curing step, at least about 40%, or at least about 50%, or at least about 60%, or at least about 75%, or at least about 90% of the polyethylene oxide in the formulation melts. In a preferred embodiment, about 100% of the polyethylene oxide melts.

  In other embodiments, the curing step includes subjecting the formulation to an elevated temperature for a specified time. In such embodiments, the curing temperature is at least as high as the softening temperature of polyethylene oxide. According to certain embodiments, the curing temperature is at least about 60 ° C, at least about 62 ° C, from about 62 ° C to about 90 ° C, from about 62 ° C to about 85 ° C, from about 62 ° C to about 80 ° C, from about 65 ° C. It is in the range of about 90 ° C, about 65 ° C to about 85 ° C, or about 65 ° C to about 80 ° C. The curing temperature is preferably about 68 ° C to about 90 ° C, about 68 ° C to about 85 ° C, about 68 ° C to about 80 ° C, about 70 ° C to about 90 ° C, about 70 ° C to about 85 ° C, about 70 ° C. To about 80 ° C, about 72 ° C to about 90 ° C, about 72 ° C to about 85 ° C, or about 72 ° C to about 80 ° C. The curing temperature can be at least about 60 ° C, at least about 62 ° C, less than about 90 ° C, or less than about 80 ° C. Preferably, the curing temperature ranges from about 62 ° C to about 72 ° C or from about 68 ° C to about 72 ° C. Preferably, the curing temperature is at least as high as the lower limit of the softening temperature range of polyethylene oxide, or at least about 62 ° C, or at least about 68 ° C. More preferably, the curing temperature is within the softening temperature range of polyethylene oxide, or at least about 70 ° C. In further embodiments, the curing temperature is at least as high as the upper limit of the softening temperature range of polyethylene oxide, or at least about 72 ° C. In further embodiments, the curing temperature is above the upper limit of the softening temperature range of polyethylene oxide, or at least about 75 ° C, or at least about 80 ° C.

  In these embodiments, where the curing step includes subjecting the formulation to elevated temperatures for a particular time, this time is hereinafter referred to as the curing time. In the measurement of the curing time, the starting and ending points of the curing step are defined. For the purposes of the present invention, the starting point of the curing step is defined as the point at which the curing temperature has been reached.

  In certain embodiments, the temperature profile during the curing step exhibits a flat-like pattern between the cure start and end points. In such embodiments, the end point of the curing step is stopped, or at least reduced, followed by, for example, terminating or reducing the heating and / or starting the next cooling step. The temperature is defined as the point at which the temperature falls above about 10 ° C., below the curing temperature, and / or below the lower limit of the softening temperature range of polyethylene oxide, eg, below about 62 ° C. When the curing temperature is reached and as a result, the curing step is initiated, deviations from the curing temperature can occur during the curing step. Such deviations are permissible as long as values of about ± 10 ° C., preferably about ± 6 ° C., and preferably about ± 3 ° C. are not exceeded. For example, if the curing temperature must be maintained at least about 75 ° C., the measured temperature can be temporarily increased to a value of about 85 ° C., about 81 ° C., or about 78 ° C., where the measured temperature is In particular, it can be lowered to a value of about 65 ° C., about 69 ° C. or about 72 ° C. If the temperature drops significantly and / or if the temperature falls below the lower limit of the softening temperature range of polyethylene oxide, for example below about 62 ° C., the curing step is stopped, ie the end point is reached. Curing can be resumed once the curing temperature is reached again.

  In other embodiments, the temperature characteristics during the curing step exhibit a parabola or a triangle between the curing start and end points. This means that after the starting point, i.e. the point at which the curing temperature is reached, the temperature rises further, reaches a maximum and then decreases. In such embodiments, the end point of the curing step is defined as the point at which the temperature drops below the curing temperature.

  Depending on the equipment used for curing (ie, the curing tool), various temperatures within the curing tool can be measured to characterize the curing temperature.

  In certain embodiments, the curing step can be performed in an oven. In such an embodiment, the temperature inside the oven is measured. Based on this, when the curing step is performed in an oven, the curing temperature is defined as the target internal temperature of the oven, and the starting point of the curing step is defined as the time when the oven internal temperature reaches the curing temperature. The end point of the curing step is (1) to stop or at least reduce the heating, and then the temperature inside the oven is only over about 10 ° C. with a flat-like temperature characteristic and / or the softening temperature range of high molecular weight polyethylene oxide. Is defined as the time when the temperature inside the oven has dropped below the curing temperature in a parabolic or triangular temperature characteristic. Preferably, the curing step is initiated when the temperature inside the oven reaches a curing temperature of at least about 62 ° C, at least about 68 ° C, at least about 70 ° C, at least about 72 ° C or at least about 75 ° C. In preferred embodiments, the temperature characteristics during the curing step exhibit a flat-like mold and the curing temperature, ie, the oven internal temperature, is at least about 68 ° C., about 70 ° C., about 72 ° C., about 73 ° C., or Within the range of about 70 ° C. to about 75 ° C., and the curing time is preferably about 30 minutes to about 20 hours, about 30 minutes to about 15 hours, about 30 minutes to about 4 hours, or about 30 minutes to about 2 hours. Range. In certain embodiments, the cure time ranges from about 30 minutes to about 90 minutes.

  In certain other embodiments, the curing step is heated in an air stream and is performed in a curing device that includes a heated air supply (inlet) and outlet, such as a coating pan or fluidized bed. Such a curing device is hereinafter referred to as a convection curing device. In such a curing device, the temperature of the inlet air, i.e. the temperature of the heated air entering the convection curing device and / or the temperature of the outlet air, i.e. the temperature of the air leaving the convection curing device can be measured. For example, by using an infrared temperature measuring instrument (such as an IR gun) or by measuring the temperature with a temperature probe placed inside the curing instrument near the formulation, the formulation inside the convection curing instrument during the curing step The temperature can also be measured or at least estimated. Based on this, if the curing step is performed in a convection curing instrument, the curing temperature can be defined and the curing time can be measured as follows.

  In one embodiment (Method 1), the curing temperature is defined as the target temperature of the inlet air, and the starting point of the curing step is defined as the time when the temperature of the inlet air reaches the curing temperature. The end point of the curing step is (1) to stop or at least reduce the heating, and then the temperature of the inlet air is a flat-like temperature characteristic, only above about 10 ° C. and / or the softening temperature of the high molecular weight polyethylene oxide Defined below the lower limit of the range, for example, less than about 62 ° C., below the cure temperature, or (2) the point at which the inlet air temperature falls below the cure temperature in a parabolic or triangular temperature characteristic. Preferably, the curing step is initiated according to Method 1 when the inlet air temperature reaches a curing temperature of at least about 62 ° C, at least about 68 ° C, at least about 70 ° C, at least about 72 ° C, or at least about 75 ° C. To do. In a preferred embodiment, the temperature characteristics during the curing step exhibit a flat-like shape, and the curing temperature, ie, the target temperature of the inlet air, is preferably at least about 72 ° C. For example, when the temperature is about 75 ° C., the cure time measured according to Method 1 is preferably in the range of about 15 minutes to about 2 hours or about 30 minutes or about 1 hour.

  In another embodiment (Method 2), the curing temperature is defined as the target temperature of the outlet air, and the starting point of the curing step is defined as the time when the temperature of the outlet air reaches the curing temperature. The end point of the curing step is (1) to stop or at least reduce heating, and then the temperature of the outlet air is only about 10 ° C. and / or below the lower limit of the softening temperature range of high molecular weight polyethylene oxide ( Flat-like temperature characteristics (eg, less than about 62 ° C.), defined as the time when the temperature drops below the curing temperature, or (2) the time when the temperature of the outlet air decreases below the curing temperature, with a parabolic or triangular temperature characteristic. The Preferably, the curing step is initiated according to Method 2 when the temperature of the outlet air reaches a curing temperature of at least about 62 ° C, at least about 68 ° C, at least about 70 ° C, at least about 72 ° C, or at least about 75 ° C. To do. In preferred embodiments, the temperature characteristics during the curing step exhibit a flat-like pattern, and the curing temperature, ie, the target temperature of the outlet air, is at least about 68 ° C., at least about 70 ° C., or at least about 72 ° C. For example, if the target temperature of the outlet air is about 68 ° C., about 70 ° C., about 72 ° C., about 75 ° C. or about 78 ° C., the cure time measured according to Method 2 is preferably about 1 minute to about 2 hours. Or in the range of about 5 minutes to about 90 minutes. For example, the curing time is about 5 minutes, about 10 minutes, about 15 minutes, about 30 minutes, about 60 minutes, about 70 minutes, about 75 minutes or about 90 minutes. In a more preferred embodiment, the cure time measured according to Method 2 ranges from about 15 minutes to about 1 hour.

  Further, in certain embodiments (Method 3), the curing temperature is defined as the target temperature of the formulation, and the origin of the curing step is the time at which the formulation temperature reaches the curing temperature, which can be measured, for example, by an IR gun. Defined. The end point of the curing step is (1) stopping or at least reducing heating, followed by a temperature of the formulation with a flat-like temperature profile, only above about 10 ° C. and / or in the softening temperature range of high molecular weight polyethylene oxide. Defined below the lower limit (eg, less than about 62 ° C.), when the temperature drops below the cure temperature, or (2) when the temperature of the formulation drops below the cure temperature in a parabolic or triangular temperature profile. Preferably, the curing step is initiated according to Method 3 when the temperature of the formulation reaches a curing temperature of at least about 62 ° C, at least about 68 ° C, at least about 70 ° C, at least about 72 ° C, or at least about 75 ° C.

  In yet another embodiment (Method 4), the curing temperature is defined as a target temperature measured using a temperature probe such as a wire thermocouple that is placed inside the curing device near the formulation and the origin of the curing step is: The temperature measured using the temperature probe is defined as the point at which the curing temperature is reached. The end point of the curing step is (1) to stop or at least reduce the heating, and then the temperature measured using the temperature probe is a flat-like temperature characteristic, only above about 10 ° C. and / or polyethylene oxide. Below the lower limit of the softening temperature range (for example, less than about 62 ° C.), when the temperature falls below the curing temperature, or (2) the temperature measured using the temperature probe is less than the curing temperature with a parabolic or triangular temperature characteristic Defined as the time of decline. Preferably, when the temperature measured using the temperature probe exhibits a temperature of at least about 62 ° C., at least about 68 ° C., at least about 70 ° C., at least about 72 ° C. or at least about 75 ° C. in the curing tool, Start the curing step. In a preferred embodiment, the temperature characteristics during the curing step exhibit a flat-like mold, and the curing temperature is at least about 68 ° C. For example, when the temperature is about 70 ° C., the cure time measured according to Method 4 is preferably in the range of about 15 minutes to about 2 hours or about 60 minutes to about 90 minutes.

  When curing is done with a convection curing device, the curing time can be measured by any of the methods described above.

  In certain embodiments, the curing temperature is defined as the target temperature range. For example, the curing temperature is defined as the target temperature range of the inlet air or the target temperature range of the outlet air. In such embodiments, the origin of the curing step is defined as the point at which the lower limit of the target temperature range is reached, and the endpoint of the curing step is to stop or at least reduce heating, followed by a temperature of about 10 ° C. It is defined as the point at which the temperature falls below the lower limit of the target temperature range only above and / or below the lower limit of the softening temperature range of polyethylene oxide (eg, about 62 ° C. or lower).

  The setting time, i.e. the time during which the formulation is subjected to the setting temperature, can be measured, for example, according to the method described above and is at least about 1 minute or at least about 5 minutes. Curing time may vary from about 1 minute to about 24 hours, from about 5 minutes to about 20 hours, from about 10 minutes to about 15 hours, from about 15 minutes to about 10 hours or about 30 minutes, depending on the specific formulation and curing temperature. May vary between ~ 5 hours. According to certain embodiments, the cure time varies between about 15 minutes and about 30 minutes. Further according to embodiments, the curing temperature is at least about 60 ° C, at least about 62 ° C, at least about 68 ° C, at least about 70 ° C, at least about 72 ° C or at least about 75 ° C, or from about 62 ° C to about 85 ° C. Or when varying between about 65 ° C. and about 85 ° C., the curing time is preferably at least about 15 minutes, at least about 30 minutes, at least about 60 minutes, at least about 75 minutes, at least about 90 minutes or at least about 120 minutes. is there. In preferred embodiments, the curing temperature is, for example, at least about 62 ° C, at least about 68 ° C, at least about 70 ° C, at least about 72 ° C or at least about 75 ° C, or from about 62 ° C to about 80 ° C, about 65 ° C. To about 80 ° C, about 68 ° C to about 80 ° C, about 70 ° C to about 80 ° C, or about 72 ° C to about 80 ° C, the curing time is preferably at least about 1 minute, at least about 5 minutes, At least about 10 minutes, at least about 15 minutes, or at least about 30 minutes. In certain such embodiments, the curing time can be selected to be as short as possible as long as the desired result (eg, increased tampering prevention) is obtained. For example, the curing time preferably does not exceed about 5 hours, does not exceed about 3 hours, or does not exceed about 2 hours. Preferably, the curing time ranges from about 1 minute to about 5 hours, from about 5 minutes to about 3 hours, from about 15 minutes to about 2 hours, or from about 15 minutes to about 1 hour. Any combination of cure temperature and number of cures as disclosed herein is within the scope of the present invention.

  In certain embodiments, the composition is subjected to a curing temperature only until the polyethylene oxide present in the formulation reaches its softening temperature and / or at least partially melts. In certain such embodiments, the cure time can be less than about 5 minutes, for example, the cure time is from 0 minutes to about 3 hours, from about 1 minute to about 2 hours, or from about 2 minutes to about 1 Can vary between hours. By selecting a curing device capable of instantaneously heating the polyethylene oxide in the formulation to at least its softening temperature, instantaneous curing is possible, resulting in at least partial melting of the high molecular weight polyethylene oxide. Such a curing device is, for example, an electronic oven, an ultrasonic device, a light irradiation device such as a UV irradiation device, an ultra high frequency (UHF) field or any other device known to those skilled in the art.

  The size of the formulation can determine the cure time and cure temperature required to achieve the desired modification prevention.

  In certain embodiments, the curing step reduces the density of the formulation, so that the density of the cured formulation is less than the density of the formulation before the curing step. Preferably, the density of the cured formulation is reduced by at least about 0.5% compared to the density of the uncured formulation. More preferably, the density of the cured formulation is at least about 0.7%, at least about 0.8%, at least about 1.0%, at least about 2.0% or at least about 2 compared to the density of the uncured formulation. .5% decrease.

  In certain embodiments, the solid controlled release dosage form is cured for at least 1 minute, at least 5 minutes or at least 15 minutes at a temperature of at least the softening point of polyethylene oxide.

  In other embodiments, the solid controlled release dosage form is about 1 minute to about 48 hours, about 5 minutes to about 24 hours, about 15 minutes to about 1 hour or about at least at the temperature of the softening point of polyethylene oxide. Cured for 30 minutes.

  The solid controlled release dosage form can be cured, for example, at a temperature of at least about 60 ° C., at least about 65 ° C., at least about 70 ° C., at least about 75 ° C., or at a temperature of about 72 ° C.

  In an alternative embodiment, the solid controlled release dosage form is about 60 ° C to about 90 ° C, about 62 ° C to about 72 ° C, about 65 ° C to about 85 ° C, about 70 ° C to about 80 ° C, about 75 ° C. It can be cured at a temperature of from about 80 ° C or from about 70 ° C to about 75 ° C.

Flattening Procedure In certain embodiments, the dosage forms of the invention can be flattened without substantially compromising the release of the opioid antagonist and agonist or the integrity of the dosage form. Flatness is described by the minimum diameter thickness of the flattened shape compared to the minimum diameter thickness of the non-planarized shape. This comparison can be based on either (i) the minimum diameter thickness of the non-planarized shape if the initial shape is non-spherical, or (ii) the diameter thickness if the initial shape is spherical. , Expressed in% thickness. Thickness can be measured using a thickness meter (eg, a digital thickness meter or a digital caliper). The planarizing force can be applied by any possible method. For the purpose of testing the dosage form of the present invention, a carve bench press can be used (unless otherwise indicated) to achieve the targeted flatness or thickness reduction. According to certain embodiments of the present invention, flattening does not break and separate the dosage form, but edge splitting and cracking can occur.

  In certain embodiments of the invention, a hammer can be used to flatten the dosage form. In such a process, the hammer strike can be applied manually from the substantially vertical direction of the dosage form to the thickest surface. The flatness is then described in the same way as disclosed above.

  In other embodiments, planarization is performed using a Schleuniger App, as described in Remington's Pharmaceutical Sciences, 18th edition, 1990, Chapter 89 “Oral Solid Dosage Forms”, pages 1633-1665, for break strength or hardness testing. be able to. In such an embodiment, the dosage form is pressed between a set of parallel plates, so that a force is applied to the substantially vertically thickest surface of the dosage form, thereby causing the dosage form to Flattened. Planarization of the dosage form can be described by% planarization based on the thickness of the planarized surface prior to performing the break strength test. Break strength (or hardness) is defined as the force at which the dosage form being tested breaks. A dosage form that does not break but is deformed by the applied force is considered to be fracture resistant at that particular force.

  Furthermore, a test for quantifying the strength of the dosage form is a texture analyzer test such as TA-XT2 Texture Analyzer (Texture Technologies Corp., 18 Fairview Road, Scarsdale, NY 10583). In this method, the dosage form is placed on a slightly recessed stainless steel stand and penetrated by a Texture Analyzer descent probe such as a TA-8A 1/8 inch diameter stainless steel ball probe. Before starting the measurement, the dosage form is aligned directly under the probe, so that it penetrates the tablet at the center of the descending probe, i.e. at the center of the dosage form, and as a result substantially against the diameter. The force of the descent probe is applied vertically and substantially in accordance with the thickness of the dosage form. First, the Texture Analyzer probe begins to move toward the dosage form sample at a pre-test speed. When the probe contacts the dosage form surface and reaches the trigger force set, the probe continues to move at the test speed and penetrates the dosage form. For each penetration depth or distance of the probe, the corresponding force is measured. When the probe reaches the desired maximum penetration depth, it changes direction and returns at post-test speed while further measurements are taken. The crack force is defined as the first local maximum force reached in the corresponding force / distance diagram and is calculated using, for example, Texture Analyzer software “TextureExpected, Version 2.64 English”.

  For the purposes of certain embodiments of the present invention, the term “crack resistance” refers to a bench press, as described above, having a thickness of about 60% or less, a thickness of about 50% or less, about Agent capable of at least planarization without breaking to a thickness of 40% or less, a thickness of about 30% or less, a thickness of about 20% or less, a thickness of about 10% or less, or a thickness of about 5% or less Defined as shape.

  In an embodiment with an opioid agonist, the amount of opioid agonist released from the planarizer form in 0.5 hours is simulated by in-vitro elution of USP Apparatus 1 (basket) at 37 ° C. without enzyme (SGF). The amount released from the non-flattening agent form in 0.5 hours, measured at 100 rpm, in 900 ml of gastric juice deviates from about 10% point, 15% point or 20% point.

In this embodiment, the solid controlled release dosage form can be flattened without breaking, and the thickness of the dosage form after planarization is no more than about 60% of the thickness of the dosage form before planarization, About 50% or less of the pre-planarized dosage form thickness, about 40% or less of the pre-planarized dosage form thickness, about 30% or less of the pre-planarized dosage form thickness, or before planarization It corresponds to about 20% or less of the thickness of the dosage form.

  The following examples are set forth to assist in understanding the invention and should not be construed as specifically limiting the invention described and claimed herein. Such modifications of the present invention, including substitutions of all equivalents now known or later developed, are within the scope of those skilled in the art, and minor changes in formulation or experimental design are It is considered to be within the scope of the present invention incorporated in the specification.

  The invention will be described more fully with reference to the accompanying examples. However, the following description is merely illustrative and should not be construed as limiting the present invention in any way.

Example 1 (prophetic)
400 mg tablets (Tablet A) containing 20 mg hydrocodone hydrogen tartrate and 6.5 mg naloxone hydrochloride were prepared using high molecular weight polyethylene oxide (PEO 303, molecular weight 7,000,000) as described in Table 1 below. To do.

  To prepare the core, the single station Manesty Type F3 tablet molding machine is equipped with a 7.94 mm circular, standard concave tool. A powder fraction of the core formulation described in Table 1 above is weighed to a target weight of 200 mg, placed in a die and compressed to form the core of tablet A.

  To prepare the shell, the single station Manesty Type F3 tablet press is equipped with a 10.32 mm circular, standard concave tool. 100 mg of the shell formulation described in Table 1 was placed in a die. The tablet core prepared as described above is manually placed in the middle of the die (on the powder bed) and an additional 100 mg of the shell formulation is placed on the tablets in the die. The material is then manually compressed by rotating the compression wheel to form the compression coated tablet A.

  Several compression coated tablets A tablets prepared as described above are placed on a tray, placed in a Hotpack model 435304 oven, and cured at a target temperature of 72 ° C. for 30 minutes.

Example 2 (prophetic)
A 500 mg tablet (Tablet B) containing 40 mg oxycodone hydrochloride and 4.5 mg naloxone hydrochloride is prepared using high molecular weight polyethylene oxide (PEO 303, molecular weight 7,000,000) as described in Table 2 below. .

  To prepare the core, the single station Manesty Type F3 tablet molding machine is equipped with a 8.73 mm circular, standard concave tool. The powder fraction of the core formulation described in Table 2 above is weighed to a target weight of 300 mg, placed in a die and compressed to form the core of tablet B.

  To prepare the shell, the single station Manesty Type F3 tablet press is equipped with a 11.11 mm circular, standard concave tool. A first portion of the 200 mg shell formulation described in Table 2 is placed in a die. The tablet core prepared as described above is manually placed in the middle of the die (on the powder bed) and the remaining 200 mg of the shell formulation is placed on the tablets in the die. The material is then manually compressed by rotating the compression wheel to form a compression coated tablet B.

  Several compression coated tablets B, prepared as described above, are placed on a tray and placed in a Hotpack model 435304 oven and cured at a target temperature of 72 ° C. for 30 minutes.

  The present invention is not to be limited in scope by the specific embodiments disclosed in the examples, which are intended as illustrative illustrations of certain aspects of the invention, and any embodiment that is functionally equivalent. Is within the scope of the present invention. Indeed, various modifications of the invention in addition to those shown and described herein will be apparent to those skilled in the art and are intended to fall within the scope of the appended claims.

Claims (76)

  A solid controlled release dosage form comprising a core comprising a core portion of an opioid antagonist and a shell enclosing the core and comprising a shell portion of the opioid antagonist, wherein the core portion of the opioid antagonist The solid controlled release dosage form wherein the release characteristics of the solid differ from the release characteristics of the opioid antagonist shell.   2. The solid controlled release dosage form of claim 1, wherein the release profile is defined by the amount of the opioid antagonist released from the dosage form.   The solid controlled release dosage form of claim 1, wherein the release profile is defined by the release rate of the opioid antagonist released from the dosage form.   2. The solid controlled release dosage form of claim 1, wherein the release profile is defined as the duration of release of the opioid antagonist released from the dosage form.   The solid controlled release dosage form of claim 2, wherein the amount of antagonist in the core is greater than the amount of antagonist in the shell.   The solid controlled release dosage form of claim 2, wherein the amount of antagonist in the core is less than the amount of antagonist in the shell.   4. The solid controlled release dosage form of claim 3, wherein the release rate of the antagonist from the core is greater than the release rate of the antagonist from the shell.   4. The solid controlled release dosage form of claim 3, wherein the release rate of the antagonist from the core is less than the release rate of the antagonist from the shell.   5. The solid controlled release dosage form of claim 4, wherein the duration of antagonist release from the core is longer than the duration of antagonist release from the shell.   5. The solid controlled release dosage form of claim 4, wherein the duration of antagonist release from the core is shorter than the duration of antagonist release from the shell.   The antagonist in the core and the antagonist in the shell are independently selected from the group consisting of naltrexone, naloxone, nalmefene, cyclazocine, levalorphan, pharmaceutically acceptable salts thereof and mixtures thereof. The solid controlled release dosage form according to any one of claims 1 to 10.   The solid controlled-release dosage form according to any one of claims 1 to 11, wherein the opioid antagonist in the core is the same as the opioid antagonist in the shell.   The solid controlled release dosage form according to any one of claims 1 to 11, wherein the opioid antagonist in the core is different from the opioid antagonist in the shell.   The solid controlled-release dosage form according to any one of claims 1 to 11, wherein the opioid antagonist in the core and the shell are both naloxone or a pharmaceutically acceptable salt thereof.   15. A solid controlled release dosage form according to any one of the preceding claims, wherein the amount of antagonist in the shell is an amount effective to prevent abuse of the dosage form.   15. A solid controlled release dosage form according to any one of the preceding claims, wherein the amount of antagonist in the shell is an amount effective to prevent intravenous abuse of the dosage form.   15. A solid controlled release dosage form according to any one of the preceding claims, wherein the amount of antagonist in the shell is an amount effective to prevent nasal abuse of the dosage form.   The solid controlled-release dosage form according to claim 1, further comprising an opioid analgesic.   19. The solid controlled release dosage form of any one of claims 1-18, wherein the opioid antagonist in the core is an amount effective to block opioid-induced adverse effects.   20. The solid controlled release dosage form of claim 19, wherein the opioid antagonist in the core is in an amount effective to prevent opioid-induced constipation.   21. A solid controlled release dosage form according to any one of the preceding claims, wherein the opioid antagonist in the core is at least partially released in the colon.   22. A solid controlled release dosage form according to any one of the preceding claims, wherein the core comprises the core portion of an opioid antagonist dispersed in a first matrix material.   22. A solid controlled release dosage form according to any one of the preceding claims, wherein the shell comprises the shell portion of an opioid antagonist dispersed in a second matrix material.   The core comprises the core portion of an opioid antagonist dispersed in a first matrix material, and the shell comprises the shell portion of an opioid antagonist dispersed in a second matrix material. 22. A solid controlled release dosage form according to any one of 21.   25. A solid controlled release dosage form according to any one of claims 1 to 24, wherein the core is a compressed tablet.   26. A solid controlled release dosage form according to any one of the preceding claims, wherein the shell is a compression coating.   24. The solid controlled release dosage form of claim 22, wherein the first matrix material comprises polyethylene oxide.   24. The solid controlled release dosage form of claim 23, wherein the second matrix material comprises polyethylene oxide.   25. The solid controlled release dosage form of claim 24, wherein the first matrix material and the second matrix material both comprise polyethylene oxide.   30. The solid controlled release dosage form of claim 29, wherein the polyethylene oxide in the second matrix material has a higher average molecular weight than the polyethylene oxide in the first matrix material.   31. Controlled release of a solid according to any one of claims 27 and 29-30, wherein the first matrix material comprises polyethylene oxide having an average molecular weight of about 300,000 daltons to about 10,000,000 daltons. Mold dosage form.   31. Controlled release of a solid according to any one of claims 27 and 29-30, wherein the first matrix material comprises polyethylene oxide having an average molecular weight of about 500,000 daltons to about 1,000,000 daltons. Mold dosage form.   31. The solid of any one of claims 28 and 29-30, wherein the second matrix material comprises polyethylene oxide having an average molecular weight of about 1,000,000 daltons to about 10,000,000 daltons. Controlled release dosage form.   31. The solid of any of claims 28 and 29-30, wherein the second matrix material comprises polyethylene oxide having an average molecular weight of about 6,000,000 daltons to about 8,000,000 daltons. Controlled release dosage form.   The polyethylene oxide in the second matrix material has an average molecular weight of about 4,000,000 daltons to about 10,000,000 daltons, and the polyethylene oxide in the first matrix material is about 300,000 daltons 31. The solid controlled release dosage form of claim 29 or 30, having an average molecular weight of from about 3,000,000 daltons.   The polyethylene oxide in the second matrix material has an average molecular weight of about 6,000,000 daltons to about 8,000,000 daltons, and the polyethylene oxide in the first matrix material is about 500,000 daltons 31. A solid controlled release dosage form according to claim 29 or 30 having an average molecular weight of from about 1,000,000 Daltons.   37. The solid controlled release dosage form of any one of claims 1-36, wherein the weight ratio of the core to the shell is from about 10: 1 to about 1:10.   38. The solid controlled release dosage form of claim 37, wherein the weight ratio of the core to the shell is from about 5: 1 to about 1: 5.   38. The solid controlled release dosage form of claim 37, wherein the weight ratio of the core to the shell is from about 2: 1 to about 1: 5.   38. The solid controlled release dosage form of claim 37, wherein the weight ratio of the core to the shell is from about 1: 0.6 to about 1: 1.5.   38. The solid controlled release dosage form of claim 37, wherein the weight ratio of the core to the shell is from about 1: 0.8 to about 1: 1.2.   42. The solid controlled release dosage form of any one of claims 19 to 41, further comprising an opioid analgesic.   43. The solid controlled release dosage form of claim 42, wherein the weight ratio of opioid analgesic to polyethylene oxide in the first matrix material of the core portion is from about 2: 1 to about 1: 100.   43. The solid controlled release dosage form of claim 42, wherein the weight ratio of opioid analgesic to the polyethylene oxide in the first matrix material of the core portion is from about 1: 1 to about 1:10.   43. The solid controlled release dosage form of claim 42, wherein the weight ratio of opioid analgesic to the polyethylene oxide in the first matrix material of the core portion is from about 1: 1.5 to about 1: 4.   43. The solid controlled release dosage form of claim 42, wherein the weight ratio of the shell portion of the opioid analgesic to polyethylene oxide in the second matrix material is from about 1: 2 to about 1: 200.   43. The solid controlled release dosage form of claim 42, wherein the weight ratio of the shell portion of opioid analgesic to polyethylene oxide in the second matrix material is from about 1: 5 to about 1:50.   43. The solid controlled release dosage form of claim 42, wherein the weight ratio of the shell portion of the opioid analgesic to polyethylene oxide in the second matrix material is from about 1:12 to about 1:25.   43. The solid controlled release dosage form of claim 18 or 42, wherein the opioid analgesic in the core is the same as the opioid analgesic in the shell.   43. The solid controlled release dosage form of claim 18 or 42, wherein the opioid analgesic in the core is different from the opioid analgesic in the shell.   43. The solid controlled release dosage form of claim 18 or 42, wherein the weight ratio of the opioid analgesic in the core to the opioid analgesic in the shell is from about 1: 1 to about 10: 1.   43. The solid controlled release dosage form of claim 18 or 42, wherein the weight ratio of the opioid analgesic in the core to the opioid analgesic in the shell is from about 2: 1 to about 8: 1.   43. The solid controlled release dosage form of claim 18 or 42, wherein the weight ratio of the opioid analgesic in the core to the opioid analgesic in the shell is from about 2: 1 to about 5: 1.   The opioid analgesic agent is alfentanil, allylprozin, alphaprozin, anileridine, benzylmorphine, vegetramide, buprenorphine, butorphanol, clonitazen, codeine, desomorphin, dextromoramide, dezocine, diapromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol , Dimefeptanol, dimethylthiambutene, dioxafetil butyrate, dipipanone, eptazosin, etoheptadine, ethylmethylthiambutene, ethylmorphine, etonithazen, etorphine, dihydroethorphine, fentanyl and derivatives, hydrocodone, hydromorphone, Hydroxypetidine, Isomethadone, Ketobemidone, Levorphanol, Levophenacylmol , Lofentanyl, meperidine, meptazinol, metazocine, methadone, methopone, morphine, mylofin, narcein, nicomorphine, norlevorphanol, normethadone, nalolphine, nalbufen, normorphin, norpipanone, opium, oxycodone, oxymorphone, papaveretam, pentazocine , Phenadoxone, phenomorphan, phenazosin, phenoperidine, pimidine, pyritramide, profeptadine, promedol, properidine, propoxyphene, sufentanil, thyridine, tramadol, pharmaceutically acceptable salts thereof, and mixtures thereof 43. A solid controlled release dosage form according to claim 18 or 42 selected from.   43. The opioid analgesic is selected from the group consisting of codeine, hydrocodone, hydromorphone, morphine, oxycodone, oxymorphone, tramadol, pharmaceutically acceptable salts thereof, and mixtures thereof. The solid controlled release dosage form described.   43. A solid controlled release dosage form according to claim 18 or 42, wherein the opioid analgesic is selected from the group consisting of hydrocodone, pharmaceutically acceptable salts thereof, derivatives and mixtures thereof.   57. The solid controlled release dosage form of claim 56, wherein the opioid analgesic is hydrocodone hydrogen tartrate.   58. The solid controlled release dosage form of claim 57, wherein the total amount of hydrocodone bitartrate in the dosage form is from about 0.5 mg to about 1250 mg.   58. The solid controlled release dosage form of claim 57, wherein the total amount of hydrocodone bitartrate in the dosage form is from about 2 mg to about 200 mg.   58. The solid controlled release dosage form of claim 57, wherein the total amount of hydrocodone bitartrate in the dosage form is from about 16 mg to about 120 mg.   43. A solid controlled release dosage form according to claim 18 or 42, wherein the opioid analgesic is selected from the group consisting of oxycodone bases, pharmaceutically acceptable salts thereof, derivatives and mixtures thereof.   62. The solid controlled release dosage form of claim 61, wherein the opioid analgesic is oxycodone hydrochloride.   64. The solid controlled release dosage form of claim 62, wherein the total amount of oxycodone hydrochloride in the dosage form is from about 2.5 mg to about 320 mg.   64. The solid controlled release dosage form of claim 62, wherein the total amount of oxycodone hydrochloride in the dosage form is from about 5 mg to about 240 mg.   64. The solid controlled release dosage form of claim 62, wherein the total amount of oxycodone hydrochloride in the dosage form is from about 5 mg to about 80 mg.   66. The solid controlled release dosage form of claims 1-65, wherein the shell portion of the antagonist is an immediate release form.   67. The solid controlled release dosage form of claims 1-66, wherein the core portion of the antagonist is a controlled release form.   67. The solid controlled release dosage form of claims 1-66, wherein the core portion of the antagonist is a delayed release form.   67. The solid controlled release dosage form of claims 1-66, wherein the core portion of the antagonist is in immediate release form and does not begin to release until a lag time after administration.   67. The solid controlled release dosage form of claims 1-66, wherein the core portion of the antagonist is in sustained release form and does not begin to release until a lag time after administration.   43. The solid controlled release dosage form of claim 18 or 42, wherein the opioid analgesic provides a therapeutic effect for about 8 hours to about 24 hours.   Weight of opioid analgesic released from the dosage form in 2 hours by in-vitro elution of USP Apparatus 1 (basket), measured at 100 rpm in 900 ml of simulated gastric fluid without enzyme (SGF) at 37 ° C. Less than about 25%, and the amount of opioid analgesic released from the dosage form in 4 hours is from about 10% to about 30%, and the amount of opioid analgesic released from the dosage form in 8 hours. The amount is about 20% to about 60%, and the amount of opioid analgesic released from the dosage form in 12 hours is about 40% to about 90%, and released from the dosage form in 18 hours. 72. The solid controlled release dosage form of claim 71, wherein the amount of opioid analgesic is greater than about 70%.   75. A method of treating pain in a subject in need of treatment comprising administering to the subject a solid controlled release dosage form according to any one of claims 18-72.   A method of preparing a solid controlled release dosage form comprising preparing a core comprising a core portion of an opioid antagonist, and wrapping the core with a shell comprising a shell portion of the opioid antagonist, comprising: The method, wherein the release characteristics of the core portion of the drug are different from the shell partial release characteristics of the opioid antagonist.   Preparing a core comprising a core portion of an opioid antagonist dispersed in a first matrix material, and encapsulating the core with a shell comprising a shell portion of the opioid antagonist dispersed in a second matrix material. A method of preparing a solid controlled release dosage form, wherein the release characteristics of the core portion of the opioid antagonist are different from the release characteristics of the shell portion of the opioid antagonist.   Use of an opioid antagonist in the preparation of a medicament according to any one of claims 1 to 72.